DESCRIPTION (from the application): The mitochondrial theory of aging proposes that oxidative damage to mitochondria is an important causal factor in the aging process. Although the mitochondrial theory of aging is an attractive hypothesis, all of the current evidence in support of this theory is essentially correlative. The basic object of the research described in this application is to test mitochondrial theory of aging using knockout/transgenic mouse models in which the balance between prooxidants and antioxidants is altered in the mitochondria to accelerate or retard the steady-state accumulation of oxidative damage. We will use knockout/transgenic mice that have altered expression of two of the antioxidant enzymes that protect the mitochondria from oxidative damage, MnSOD and phospholipid hydroperoxide gluathione peroxidase (PHGPx). Transgenic mice overexpressing MnSOD (hSOD2+/-) will be used to decrease the steady-state accumulation of oxidative damage in mitochondria and knockout mice that have reduced expression of PHGPx (GPx4+/-) will be used to increase the steady-state accumulation of oxidative damage in mitochondria. These knockout/transgenic mice will be used to test the following hypothesis: an altered steady-state accumulation of oxidative damage with age in mitochondria will result in altered mitochondria function that will lead to an alteration in aging and age-related pathology. The specific aims of this study are: 1 ) To produce transgenic mice that overexpress MnSOD using clones isolated from a human genomic library containing the SOD2 gene, 2) To measure the age-related changes in the steady-state levels of oxidative damage in mice with either enhanced MnSOD activity or reduced PHGPx activity, 3) To measure the age-related changes in mitochondria function and turnover in mice with either enhanced MnSOD activity or reduced PHGPx activity, and 4) To measure the survival and pathology of the hSOD2+/+ and the GPx4+/- mice compared to wild type mice.